Nickolas Papadopoulos

Multiyear Clinical Outcomes of Cancers Diagnosed Following Detection by a Blood-Based Multicancer Early Detection Test

Abstract In the US, <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multicancer early detection (MCED) tests offer the opportunity to expand cancer screening. Understanding the characteristics and clinical outcomes of MCED-detected cancers is critical to clarifying MCED tests’ potential impact. DETECT-A is the first prospective interventional trial of an MCED blood test (CancerSEEK). CancerSEEK, coupled with diagnostic PET-CT, identified cancers including those not detected by SoC screening, the majority of which were localized or regional. We report multiyear outcomes in patients with cancers diagnosed following a positive CancerSEEK test. Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnoses, treatments, and clinical outcomes was extracted from medical records through November 2022. Data collection occurred at a median of 4.4 years (IQR: 4.1–4.6) following study enrollment. Thirteen of 26 (50%) participants were alive and cancer-free [ovarian (4), thyroid (1), uterine (2), breast (1), colorectal (2), and lung (3)]; 7/13 (54%) had cancers without recommended SoC screening modalities. All eight treated stage I or II participants (8/8, 100%) and 12/14 (86%) surgically treated participants were alive and cancer-free. Eligibility for surgical treatment was associated with favorable multiyear outcomes (P = 0.0002). Half of participants with MCED-detected cancers were alive and cancer-free after 4.4 years median follow-up. Most were diagnosed with early-stage cancers and were treated surgically. These results suggest that early cancer detection by CancerSEEK may have facilitated curative-intent treatments and associated positive clinical outcomes in some DETECT-A participants. Prevention Relevance: This study provides preliminary evidence of the potential of multicancer early detection testing as an effective screening tool for detecting cancers without standard-of-care (SoC) screening modalities and complementing SoC cancer screening.

The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer

Abstract Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance. Significance: The origin of excess cfDNA in patients with cancer is unknown. Using cfDNA methylation patterns, we determined that neither the tumor nor the surrounding normal tissue contributes this excess cfDNA—rather it comes from leukocytes. This finding suggests that cancers have a systemic impact on cell turnover or DNA clearance. See related commentary by Thierry and Pisareva, p. 2122. This article is featured in Selected Articles from This Issue, p. 2109

Aneuploidy Landscape in Precursors of Ovarian Cancer

Abstract Purpose: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. Experimental Design: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology. Results: We found that nearly all p53 signatures lost the entire Chr17, offering a “two-hit” mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC. Conclusions: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially “aggressive” STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions

Abstract Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. In this study, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathologic features in 166 ovarian precancerous lesions. Four precancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immunoregulatory gene expression, and histologic features. Notably, the immunoreactive subtype upregulated immunoregulatory genes, exhibited chronic inflammation, and was enriched in cases with germline BRCA1/2 mutations and deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double “two-hit” involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial–mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive precancerous lesions. Significance: Integrated spatial multiomics analysis of ovarian precancerous lesions reveals molecular subtypes and mechanisms underlying tumor initiation, offering a foundation for future risk stratification and prevention. See related commentary by Soong et al. p. 1537